The eye is an immunologically privileged site where transplanted tissues survive much longer than in conventional sites, such as the skin. Moreover, both cellular and soluble antigens placed in the anterior chamber of the eye induce a systemic form of tolerance, called ACAID, in which delayed hypersensitivity and complement fixing antibody responses to an immunogenic form of the antigen are inhibited. Our recent studies demonstrate that the induction of cytolytic T cell responses is also profoundly suppressed in mice receiving ocular antigens. Our data also show that ocular tolerance is not induced in mice that are depleted of gamma/delta T cells and the adoptive transfer of splenic gamma/delta T cells from normal mice reconstitutes tolerance. The long-term goal of the proposed studies is to determine the mechanisms by which gamma/delta T cells regulate ocular tolerance as manifest in CD4 and CD8 T cell responses. We will test the hypothesis that ACAID inducing antigen-presenting cells and NK alpha/beta T cells are required for the activation of gamma/delta T cells in the spleen. The second aim is to test the hypothesis that gamma/delta T cells, activated in ACAID, are antigen-specific, regulatory T cells. We will determine whether gamma/delta T cells induce CD8+, alpha/beta TCR to become efferent suppressor T cells in ACAID. Whether the gamma/delta T cells (and/or CD8+ suppressor effector T cells) express memory functions will be assessed using PLAP/Cre transgenic B6 mice. Finally, a new model using ROSA26R Tg mice will be used to test the hypothesis that ACAID inducing APC can be identified and tracked in vivo. Understanding the mechanisms of ACAID may one day be used to prevent graft rejection. Immune response by previously primed individuals can be inhibited by ACAID. Hence, understanding ACAID may also provide novel treatments for patients with autoimmune diseases after their symptoms arise.